Overexpression of the HER-2/neu receptor has been linked to increased rates of relapse and metastasis in breast cancer. HER-2/neu belongs to the epidermal growth factor receptor (EGF-R) or c-erbB family of receptor tyrosine kinase, and is directly involved in tumor cell survival and proliferation. Recent studies have revealed a unique role of HER-2/neu in the regulation of tumor angiogenesis by modulating the expression of VEGF via a mechanism different from the hypoxia-induced cascade. This mechanism may explain the constitutive VEGF production by tumor cells under normoxic conditions. The HER-2/neu receptor also provides a unique target for cancer therapy with the humanized monoclonal antibody, Herceptin. The advantage of anti-HER-2/neu therapy is that it acts against multiple pathways vital for tumor survival. However, the overall response rate of breast cancers to Herceptin is just over 10%. One reason for the relatively low Herceptin efficacy can be poor tumor vascularization that results in inadequate delivery of the antibody. Another resistance mechanism, which has not been widely explored, is the effect of the tumor microenvironment on receptor expression and integrity. Acidic extracellular pH and hypoxia associated with these regions may attenuate the expression and integrity of these receptors through degradative mechanisms, resulting in less than optimum treatment outcome and subsequent tumor recurrence. The ability to detect receptor expression with MRI opens up possibilities of determining, for the first time, the relationship between receptor expression, and vascularization, metabolism, and the physiological environment. In this application, we intend to first optimize MRI detection of the HER-2/neu receptor, and subsequently use the vast array of functional MR imaging techniques to determine the role of vascularization and the physiological environment in receptor expression and receptor-targeted therapy. In addition, we intend to exploit the hypoxic environment of solid tumors and use hypoxia-targeted siRNA-based gene therapy in combination with receptor-targeted therapy, to maximize the therapeutic effect and the treatment outcome.